Breast cancer cells that preferentially metastasize to lung or bone are more glycolytic, synthesize serine at greater rates, and consume less ATP and NADPH than parent MDA-MB-231 cells
Abstract Gene expression signatures associated with breast cancer metastases suggest that metabolic re-wiring is important for metastatic growth in lungs, bones, and other organs. However, since pathway fluxes depend on additional factors such as ATP demand, allosteric effects, and post-translationa...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
BMC
2023-02-01
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| Series: | Cancer & Metabolism |
| Online Access: | https://doi.org/10.1186/s40170-023-00303-5 |
| _version_ | 1797863813047910400 |
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| author | Mika B. Jekabsons Mollie Merrell Anna G. Skubiz Noah Thornton Sandra Milasta Douglas Green Taosheng Chen Yan-Hong Wang Bharathi Avula Ikhlas A. Khan Yu-Dong Zhou |
| author_facet | Mika B. Jekabsons Mollie Merrell Anna G. Skubiz Noah Thornton Sandra Milasta Douglas Green Taosheng Chen Yan-Hong Wang Bharathi Avula Ikhlas A. Khan Yu-Dong Zhou |
| author_sort | Mika B. Jekabsons |
| collection | DOAJ |
| description | Abstract Gene expression signatures associated with breast cancer metastases suggest that metabolic re-wiring is important for metastatic growth in lungs, bones, and other organs. However, since pathway fluxes depend on additional factors such as ATP demand, allosteric effects, and post-translational modification, flux analysis is necessary to conclusively establish phenotypes. In this study, the metabolic phenotypes of breast cancer cell lines with low (T47D) or high (MDA-MB-231) metastatic potential, as well as lung (LM)- and bone (BoM)-homing lines derived from MDA-MB-231 cells, were assessed by 13C metabolite labeling from [1,2-13C] glucose or [5-13C] glutamine and the rates of nutrient and oxygen consumption and lactate production. MDA-MB-231 and T47D cells produced 55 and 63%, respectively, of ATP from oxidative phosphorylation, whereas LM and BoM cells were more glycolytic, deriving only 20–25% of their ATP from mitochondria. ATP demand by BoM and LM cells was approximately half the rate of the parent cells. Of the anabolic fluxes assessed, nucleotide synthesis was the major ATP consumer for all cell lines. Glycolytic NADH production by LM cells exceeded the rate at which it could be oxidized by mitochondria, suggesting that the malate-aspartate shuttle was not involved in re-oxidation of these reducing equivalents. Serine synthesis was undetectable in MDA-MB-231 cells, whereas 3–5% of glucose was shunted to serine by LM and BoM lines. Proliferation rates of T47D, BoM, and LM lines tightly correlated with their respiration-normalized NADPH production rates. In contrast, MDA-MB-231 cells produced NADPH and GSH at higher rates, suggesting this line is more oxidatively stressed. Approximately half to two-thirds of NADPH produced by T47D, MDA-MB-231, and BoM cells was from the oxidative PPP, whereas the majority in LM cells was from the folate cycle. All four cell lines used the non-oxidative PPP to produce pentose phosphates, although this was most prominent for LM cells. Taken together, the metabolic phenotypes of LM and BoM lines differed from the parent line and from each other, supporting the metabolic re-wiring hypothesis as a feature of metastasis to lung and bone. |
| first_indexed | 2024-04-09T22:41:40Z |
| format | Article |
| id | doaj.art-7e752c0384814035bfa0d6530ec190eb |
| institution | Directory Open Access Journal |
| issn | 2049-3002 |
| language | English |
| last_indexed | 2024-04-09T22:41:40Z |
| publishDate | 2023-02-01 |
| publisher | BMC |
| record_format | Article |
| series | Cancer & Metabolism |
| spelling | doaj.art-7e752c0384814035bfa0d6530ec190eb2023-03-22T12:08:23ZengBMCCancer & Metabolism2049-30022023-02-0111112410.1186/s40170-023-00303-5Breast cancer cells that preferentially metastasize to lung or bone are more glycolytic, synthesize serine at greater rates, and consume less ATP and NADPH than parent MDA-MB-231 cellsMika B. Jekabsons0Mollie Merrell1Anna G. Skubiz2Noah Thornton3Sandra Milasta4Douglas Green5Taosheng Chen6Yan-Hong Wang7Bharathi Avula8Ikhlas A. Khan9Yu-Dong Zhou10Department of Biology, University of MississippiDepartment of Biology, University of MississippiDepartment of Biology, University of MississippiDepartment of Biology, University of MississippiDepartment of Immunology, St Jude Children’s Research HospitalDepartment of Immunology, St Jude Children’s Research HospitalDepartment of Chemical Biology and Therapeutics, St Jude Children’s Research HospitalNational Center for Natural Products Research, School of Pharmacy, University of MississippiNational Center for Natural Products Research, School of Pharmacy, University of MississippiNational Center for Natural Products Research, School of Pharmacy, University of MississippiDepartment of Chemistry and Biochemistry, University of MississippiAbstract Gene expression signatures associated with breast cancer metastases suggest that metabolic re-wiring is important for metastatic growth in lungs, bones, and other organs. However, since pathway fluxes depend on additional factors such as ATP demand, allosteric effects, and post-translational modification, flux analysis is necessary to conclusively establish phenotypes. In this study, the metabolic phenotypes of breast cancer cell lines with low (T47D) or high (MDA-MB-231) metastatic potential, as well as lung (LM)- and bone (BoM)-homing lines derived from MDA-MB-231 cells, were assessed by 13C metabolite labeling from [1,2-13C] glucose or [5-13C] glutamine and the rates of nutrient and oxygen consumption and lactate production. MDA-MB-231 and T47D cells produced 55 and 63%, respectively, of ATP from oxidative phosphorylation, whereas LM and BoM cells were more glycolytic, deriving only 20–25% of their ATP from mitochondria. ATP demand by BoM and LM cells was approximately half the rate of the parent cells. Of the anabolic fluxes assessed, nucleotide synthesis was the major ATP consumer for all cell lines. Glycolytic NADH production by LM cells exceeded the rate at which it could be oxidized by mitochondria, suggesting that the malate-aspartate shuttle was not involved in re-oxidation of these reducing equivalents. Serine synthesis was undetectable in MDA-MB-231 cells, whereas 3–5% of glucose was shunted to serine by LM and BoM lines. Proliferation rates of T47D, BoM, and LM lines tightly correlated with their respiration-normalized NADPH production rates. In contrast, MDA-MB-231 cells produced NADPH and GSH at higher rates, suggesting this line is more oxidatively stressed. Approximately half to two-thirds of NADPH produced by T47D, MDA-MB-231, and BoM cells was from the oxidative PPP, whereas the majority in LM cells was from the folate cycle. All four cell lines used the non-oxidative PPP to produce pentose phosphates, although this was most prominent for LM cells. Taken together, the metabolic phenotypes of LM and BoM lines differed from the parent line and from each other, supporting the metabolic re-wiring hypothesis as a feature of metastasis to lung and bone.https://doi.org/10.1186/s40170-023-00303-5 |
| spellingShingle | Mika B. Jekabsons Mollie Merrell Anna G. Skubiz Noah Thornton Sandra Milasta Douglas Green Taosheng Chen Yan-Hong Wang Bharathi Avula Ikhlas A. Khan Yu-Dong Zhou Breast cancer cells that preferentially metastasize to lung or bone are more glycolytic, synthesize serine at greater rates, and consume less ATP and NADPH than parent MDA-MB-231 cells Cancer & Metabolism |
| title | Breast cancer cells that preferentially metastasize to lung or bone are more glycolytic, synthesize serine at greater rates, and consume less ATP and NADPH than parent MDA-MB-231 cells |
| title_full | Breast cancer cells that preferentially metastasize to lung or bone are more glycolytic, synthesize serine at greater rates, and consume less ATP and NADPH than parent MDA-MB-231 cells |
| title_fullStr | Breast cancer cells that preferentially metastasize to lung or bone are more glycolytic, synthesize serine at greater rates, and consume less ATP and NADPH than parent MDA-MB-231 cells |
| title_full_unstemmed | Breast cancer cells that preferentially metastasize to lung or bone are more glycolytic, synthesize serine at greater rates, and consume less ATP and NADPH than parent MDA-MB-231 cells |
| title_short | Breast cancer cells that preferentially metastasize to lung or bone are more glycolytic, synthesize serine at greater rates, and consume less ATP and NADPH than parent MDA-MB-231 cells |
| title_sort | breast cancer cells that preferentially metastasize to lung or bone are more glycolytic synthesize serine at greater rates and consume less atp and nadph than parent mda mb 231 cells |
| url | https://doi.org/10.1186/s40170-023-00303-5 |
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